Constructing Tumor Progression Pathways and Biomarker Discovery with Fuzzy Kernel Kmeans and DNA Methylation Data

Constructing pathways of tumor progression and discovering the biomarkers associated with cancer is critical for understanding the molecular basis of the disease and for the establishment of novel chemotherapeutic approaches and in turn improving the clinical efficiency of the drugs. It has recently received a lot of attention from bioinformatics researchers. However, relatively few methods are available for constructing pathways. This article develops a novel entropy kernel based kernel clustering and fuzzy kernel clustering algorithms to construct the tumor progression pathways using CpG island methylation data. The methylation data which come from tumor tissues diagnosed at different stages can be used to distinguish epigenotype and phenotypes the describe the molecular events of different phases. Using kernel and fuzzy kernel kmeans, we built tumor progression trees to describe the pathways of tumor progression and find the possible biomarkers associated with cancer. Our results indicate that the proposed algorithms together with methylation profiles can predict the tumor progression stages and discover the biomarkers efficiently. Software is available upon request

Systematic Review and Meta-Analysis on the Association Between Outpatient Statins Use and Infectious Disease-Related Mortality

Background: To update and refine systematic literature review on the association between outpatient statins use and mortality in patients with infectious disease. Materials and Methods: We searched articles published before September 31, 2012, on the association between statins and infectious disease-related mortality through electronic databases. Eligible articles were analyzed in Review Manager 5.1. We conducted stratification analysis by study design, infection types, clinical outcomes and study locations. Results: The pooled odds ratio (OR) for death (statins use vs. no use) across the 41 included studies was 0.71 (95% confidence interval: 0.64, 0.78). The corresponding pooled ORs were 0.58 (0.38, 0.90), 0.66 (0.57, 0.75), 0.71 (0.57, 0.89) and 0.83 (0.67, 1.04) for the case-control study, retrospective cohort studies, prospective cohort studies and RCTs; 0.40 (0.20, 0.78), 0.61 (0.41, 0.90), 0.69 (0.62, 0.78) and 0.86 (0.68, 1.09) for bacteremia, sepsis, pneumonia and other infections; 0.62 (0.534, 0.72), 0.68 (0.53, 0.89), 0.71 (0.61, 0.83) and 0.86 (0.70, 1.07) for 30-day, 90-day, in-hospital and long-term (>1 year) mortality, respectively. Conclusions: Outpatient statins use is associated with a lower risk of death in patients with infectious disease in observational studies, but in a less extent in clinical trials. This association also varies considerably by infection types and clinical outcomes

Passive immunotherapy for influenza A H5N1 virus infection with equine hyperimmune globulin F(ab')(2 )in mice

BACKGROUND: Avian influenza virus H5N1 has demonstrated considerable pandemic potential. Currently, no effective vaccines for H5N1 infection are available, so passive immunotherapy may be an alternative strategy. To investigate the possible therapeutic effect of antibody against highly pathogenic H5N1 virus on a mammal host, we prepared specific equine anti-H5N1 IgGs from horses vaccinated with inactivated H5N1 virus, and then obtained the F(ab')(2 )fragments by pepsin digestion of IgGs. METHODS: The horses were vaccinated with inactivated H5N1 vaccine to prepare anti-H5N1 IgGs. The F(ab')(2 )fragments were purified from anti-H5N1 hyperimmune sera by a protocol for 'enhanced pepsin digestion'. The protective effect of the F(ab')(2 )fragments against H5N1 virus infection was determined in cultured MDCK cells by cytopathic effect (CPE) assay and in a BALB/c mouse model by survival rate assay. RESULTS: By the protocol for 'enhanced pepsin digestion', total 16 g F(ab')(2 )fragments were finally obtained from one liter equine antisera with the purity of over 90%. The H5N1-specific F(ab')(2 )fragments had a HI titer of 1:1024, and the neutralization titre of F(ab')(2 )reached 1: 2048. The in vivo assay showed that 100 μg of the F(ab')(2 )fragments could protect BALB/c mice infected with a lethal dose of influenza H5N1 virus. CONCLUSION: The availability of highly purified H5N1-specific F(ab')(2 )fragments may be promising for treatment of influenza H5N1 infection. Our work has provided experimental support for the application of the therapeutic equine immunoglobulin in future large primate or human trials

Adoptive Transfer of Human Gingiva-derived Mesenchymal Stem Cells Ameliorates Collagen-induced Arthritis via Suppression of Th1 and Th17 Cells and Enhancement of Regulatory T Cell Differentiation

Objective Current approaches offer no cures for rheumatoid arthritis (RA). Accumulating evidence has revealed that manipulation of bone marrow-derived mesenchymal stem cells (BM-MSCs) may have the potential to control or even prevent RA, but BM-MSC-based therapy faces many challenges, such as limited cell availability and reduced clinical feasibility. This study in mice with established collagen-induced arthritis (CIA) was undertaken to determine whether substitution of human gingiva-derived mesenchymal stem cells (G-MSCs) would significantly improve the therapeutic effects. Methods CIA was induced in DBA/1J mice by immunization with type II collagen and Freund\u27s complete adjuvant. G-MSCs were injected intravenously into the mice on day 14 after immunization. In some experiments, intraperitoneal injection of PC61 (anti-CD25 antibody) was used to deplete Treg cells in arthritic mice. Results Infusion of G-MSCs in DBA/1J mice with CIA significantly reduced the severity of arthritis, decreased the histopathology scores, and down-regulated the production of inflammatory cytokines (interferon-γ and interleukin-17A). Infusion of G-MSCs also resulted in increased levels of CD4+CD39+FoxP3+ cells in arthritic mice. These increases were noted early after infusion in the spleens and lymph nodes, and later after infusion in the synovial fluid. The FoxP3+ Treg cells that were increased in frequency mainly consisted of Helios-negative cells. When Treg cells were depleted, infusion of G-MSCs partially interfered with the progression of CIA. Pretreatment of G-MSCs with a CD39 or CD73 inhibitor significantly reversed the protective effect of G-MSCs on CIA. Conclusion The role of G-MSCs in controlling the development and severity of CIA mostly depends on CD39/CD73 signals and partially depends on the induction of CD4+CD39+FoxP3+ Treg cells. G-MSCs provide a promising approach for the treatment of autoimmune diseases. Copyright © 2013 by the American College of Rheumatology

First identification of long non-coding RNAs in fungal parasite Nosema ceranae

International audienceAbstractNosema ceranae is a unicellular fungal parasite of honey bees and causes huge losses for apiculture. Until present, no study on N. ceranae long non-coding RNAs (lncRNAs) was documented. Here, we sequenced purified spores of N. ceranae using strand-specific library construction and high-throughput RNA sequencing technologies. In total, 83 novel lncRNAs were predicted from N. ceranae spore samples, including lncRNAs, long intergenic non-coding RNAs (lincRNAs), and sense lncRNAs. Moreover, these lncRNAs share similar characteristics with those identified in mammals and plants, such as shorter length and fewer exon number and transcript isoforms than protein-coding genes. Finally, the expression of 12 lncRNAs was confirmed with RT-PCR, confirming their true existence. To our knowledge, this is the first evidence of lncRNAs produced by a microsporidia species, offering novel insights into basic biology such as regulation of gene expression of this widespread taxonomic group

TINGKAT KEMAMPUAN SISWA TERHADAP MATERIRNMENGHARGAI PENINGGALAN SEJARAHRNKELAS IV SDN GUGUS MONTASIK

Banda Ace

Somatic mutation and gain of copy number of PIK3CA in human breast cancer

INTRODUCTION: Phosphatidylinositol 3-kinases (PI3Ks) are a group of lipid kinases that regulate signaling pathways involved in cell proliferation, adhesion, survival, and motility. Even though PIK3CA amplification and somatic mutation have been reported previously in various kinds of human cancers, the genetic change in PIK3CA in human breast cancer has not been clearly identified. METHODS: Fifteen breast cancer cell lines and 92 primary breast tumors (33 with matched normal tissue) were used to check somatic mutation and gene copy number of PIK3CA. For the somatic mutation study, we specifically checked exons 1, 9, and 20, which have been reported to be hot spots in colon cancer. For the analysis of the gene copy number, we used quantitative real-time PCR and fluorescence in situ hybridization. We also treated several breast cancer cells with the PIK3CA inhibitor LY294002 and compared the apoptosis status in cells with and without PIK3CA mutation. RESULTS: We identified a 20.6% (19 of 92) and 33.3% (5 of 15) PIK3CA somatic mutation frequency in primary breast tumors and cell lines, respectively. We also found that 8.7% (8 of 92) of the tumors harbored a gain of PIK3CA gene copy number. Only four cases in this study contained both an increase in the gene copy number and a somatic mutation. In addition, mutation of PIK3CA correlated with the status of Akt phosphorylation in some breast cancer cells and inhibition of PIK3CA-induced increased apoptosis in breast cancer cells with PIK3CA mutation. CONCLUSION: Somatic mutation rather than a gain of gene copy number of PIK3CA is the frequent genetic alteration that contributes to human breast cancer progression. The frequent and clustered mutations within PIK3CA make it an attractive molecular marker for early detection and a promising therapeutic target in breast cancer

Fluorescent Gold Nanoprobes for the Sensitive and Selective Detection for Hg2+

A simple, cost-effective yet rapid and sensitive sensor for on-site and real-time Hg2+ detection based on bovine serum albumin functionalized fluorescent gold nanoparticles as novel and environmentally friendly fluorescent probes was developed. Using this probe, aqueous Hg2+ can be detected at 0.1 nM in a facile way based on fluorescence quenching. This probe was also applied to determine the Hg2+ in the lake samples, and the results demonstrate low interference and high sensitivity

All-Trans Retinoic Acid Promotes TGF-β-Induced Tregs via Histone Modification but Not DNA Demethylation on Foxp3 Gene Locus

It has been documented all-trans retinoic acid (atRA) promotes the development of TGF-β-induced CD4(+)Foxp3(+) regulatory T cells (iTreg) that play a vital role in the prevention of autoimmune responses, however, molecular mechanisms involved remain elusive. Our objective, therefore, was to determine how atRA promotes the differentiation of iTregs.Addition of atRA to naïve CD4(+)CD25(-) cells stimulated with anti-CD3/CD28 antibodies in the presence of TGF-β not only increased Foxp3(+) iTreg differentiation, but maintained Foxp3 expression through apoptosis inhibition. atRA/TGF-β-treated CD4(+) cells developed complete anergy and displayed increased suppressive activity. Infusion of atRA/TGF-β-treated CD4(+) cells resulted in the greater effects on suppressing symptoms and protecting the survival of chronic GVHD mice with typical lupus-like syndromes than did CD4(+) cells treated with TGF-β alone. atRA did not significantly affect the phosphorylation levels of Smad2/3 and still promoted iTreg differentiation in CD4(+) cells isolated from Smad3 KO and Smad2 conditional KO mice. Conversely, atRA markedly increased ERK1/2 activation, and blockade of ERK1/2 signaling completely abolished the enhanced effects of atRA on Foxp3 expression. Moreover, atRA significantly increased histone methylation and acetylation within the promoter and conserved non-coding DNA sequence (CNS) elements at the Foxp3 gene locus and the recruitment of phosphor-RNA polymerase II, while DNA methylation in the CNS3 was not significantly altered.We have identified the cellular and molecular mechanism(s) by which atRA promotes the development and maintenance of iTregs. These results will help to enhance the quantity and quality of development of iTregs and may provide novel insights into clinical cell therapy for patients with autoimmune diseases and those needing organ transplantation